Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening

Diabetes mellitus is a complex metabolic disorder that is associated with an increased risk of breast cancer. Despite this correlation, the interplay between tumor progression and diabetes, particularly with regard to stiffening of the extracellular matrix, is still mechanistically unclear. Here, we established a murine model where hyperglycemia was induced before breast tumor development. Using the murine model, in vitro systems, and patient samples, we show that hyperglycemia increases tumor growth, extracellular matrix stiffness, glycation, and epithelial-mesenchymal transition of tumor cells. Upon inhibition of glycation or mechanotransduction in diabetic mice, these same metrics are reduced to levels comparable with nondiabetic tumors. Together, our study describes a novel biomechanical mechanism by which diabetic hyperglycemia promotes breast tumor progression via glycating the extracellular matrix. In addition, our work provides evidence that glycation inhibition is a potential adjuvant therapy for diabetic cancer patients due to the key role of matrix stiffening in both diseases.

Automated summary

This study investigates the interplay between diabetes and breast cancer, focusing on the mechanistic role of extracellular matrix stiffening. Using a murine model, in vitro systems, and patient samples, the study reveals that hyperglycemia promotes tumor growth, extracellular matrix stiffness, glycation, and the epithelial-mesenchymal transition of tumor cells. Inhibition of glycation or mechanotransduction effectively reduces these metrics in diabetic mice, suggesting that glycation inhibition could be a potential adjuvant therapy for diabetic cancer patients.